Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.

Patient-reported outcomes are important in nonalcoholic fatty liver disease (NAFLD). Pruritus is of special interest for evolving therapies with farnesoid X receptor (FXR) agonists. The aim of this study was to investigate the prevalence of pruritus in a real-life NAFLD cohort and analyze associations with anxiety and depression. Pruritus was assessed using a visual analogue- (VAS) and 5-D itch-scale (5-D). Anxiety and depression were evaluated by Beck’s-Depression-Inventory (BDI) and the Hospital Anxiety and Depression Scale (HADS-A, HADS-D). An optimal logistic regression model was found with a stepwise procedure to investigate variables associated with pruritus. In total, 123 NAFLD patients were recruited. VAS and 5-D were highly correlated (Spearman’s correlation coefficient 0.89). Moderate/severe pruritus was reported in 19% (VAS) and 21% (5-D) of patients. Anxiety and depression were present in 12% and 4% (HADS-A and HADS-D, respectively) and 12% (BDI) of cases. There was a significant association between VAS and BDI (p = 0.019). The final multivariate model for 5-D included diabetes mellitus (OR 4.51; p = 0.01), BDI (OR 5.98; p = 0.024), and HADS-A (OR 7.75; p = 0.011). One-fifth of NAFLD patients reported moderate or severe pruritus. 5-D was significantly associated with diabetes mellitus, depression, and anxiety. These findings should be tested in larger populations and considered in candidates for treatment with FXR agonists.

Mesenchymal stromal cell (MSC) transplantation ameliorated hepatic lipid load; tissue inflammation; and fibrosis in rodent animal models of non-alcoholic steatohepatitis (NASH) by as yet largely unknown mechanism(s). In a mouse model of NASH; we transplanted bone marrow-derived MSCs into the livers; which were analyzed one week thereafter. Combined metabolomic and proteomic data were applied to weighted gene correlation network analysis (WGCNA) and subsequent identification of key drivers. Livers were analyzed histologically and biochemically. The mechanisms of MSC action on hepatocyte lipid accumulation were studied in co-cultures of hepatocytes and MSCs by quantitative image analysis and immunocytochemistry. WGCNA and key driver analysis revealed that NASH caused the impairment of central carbon; amino acid; and lipid metabolism associated with mitochondrial and peroxisomal dysfunction; which was reversed by MSC treatment. MSC improved hepatic lipid metabolism and tissue homeostasis. In co-cultures of hepatocytes and MSCs; the decrease of lipid load was associated with the transfer of mitochondria from the MSCs to the hepatocytes via tunneling nanotubes (TNTs). Hence; MSCs may ameliorate lipid load and tissue perturbance by the donation of mitochondria to the hepatocytes. Thereby; they may provide oxidative capacity for lipid breakdown and thus promote recovery from NASH-induced metabolic impairment and tissue injury.

Overweight has become a major health care problem in Western societies and is accompanied by an increasing incidence and prevalence of non-alcoholic fatty liver disease (NAFLD). The progression from NAFLD to non-alcoholic steatohepatitis (NASH) marks a crucial tipping point in the progression of severe and irreversible liver diseases. This study aims to gain further insight into the molecular processes leading to the evolution from steatosis to steatohepatitis. Steatosis was induced in cultures of primary human hepatocytes by continuous five-day exposure to free fatty acids (FFAs). The kinetics of lipid accumulation, lipotoxicity, and oxidative stress were measured. Additionally, ER stress was evaluated by analyzing the protein expression profiles of its key players: PERK, IRE1a, and ATF6a. Our data revealed that hepatocytes are capable of storing enormous amounts of lipids without showing signs of lipotoxicity. Prolonged lipid accumulation did not create an imbalance in hepatocyte redox homeostasis or a reduction in antioxidative capacity. However, we observed an FFA-dependent increase in ER stress, revealing thresholds for triggering the activation of pathways associated with lipid stress, inhibition of protein translation, and apoptosis. Our study clearly showed that even severe lipid accumulation can be attenuated by cellular defenses, but regenerative capacities may be reduced.

京都大学 / 新制・課程博士 / 博士(農学) / 甲第24651号 / 農博第2534号 / 新制||農||1097(附属図書館) / 学位論文||R5||N5432(農学部図書室) / 京都大学大学院農学研究科応用生物科学専攻 / (主査)教授 太田 毅, 教授 横井 伯英, 教授 舟場 正幸 / 学位規則第4条第1項該当 / Doctor of Agricultural Science / Kyoto University / DFAM

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Game theory is the study of tactical interactions involving conflicts and cooperations among multiple decision makers called players with applications in diverse disciplines such as economics, biology, management, communication networks, electric power systems and control. This dissertation studies a statistical differential game problem where finite N players optimize their system performance by shaping the distribution of their cost function through cost cumulants. This research integrates game theory with statistical optimal control theory and considers a statistical Nash non-cooperative nonzero-sum game for a nonlinear dynamic system with nonquadratic cost functions. The objective of the statistical Nash game is to find the equilibrium solution where no player has the incentive to deviate once other players maintain their equilibrium strategy. The necessary condition for the existence of the Nash equilibrium solution is given for the m-th cumulant cost optimization using the Hamilton-Jacobi-Bellman (HJB) equations. In addition, the sufficient condition which is the verification theorem for the existence of Nash equilibrium solution is given for the m-th cumulant cost optimization using the Hamilton-Jacobi-Bellman (HJB) equations. However, solving the HJB equations even for relatively low dimensional game problem is not trivial, we propose to use neural network approximate method to find the solution of the HJB partial differential equations for the statistical game problem. Convergence proof of the neural network approximate method solution to exact solution is given. In addition, numerical examples are provided for the statistical game to demonstrate the applicability of the proposed theoretical developments. / Electrical and Computer Engineering

In this study, I introduce the alternative-dependent focal Luce model (ADFLM), a random choice model generalizing the well-known Luce model (1959). In the ADFLM, focal alternatives are chosen more frequently relative to their utilities. I identify utilities, focal sets, and the magnitude of focal biases from choice data. Additionally, I axiomatically characterize the ADFLM by weakening the independence of irrelevant alternatives (IIA) axiom. This model can explain the well-known behavioral phenomena, the attraction and compromise effects. Furthermore, I also study the seller's profit maximization problem in the ADFLM. I also study an asymmetric dynamic patent race with a deadline under complete information. In my model, two firms decide whether to invest in RandD. The patent arrives randomly according to a Poisson process, and the large firm has a higher hazard rate than the small firm. I find the unique sub-game perfect Nash equilibrium strategy for this game. At the equilibrium, the large firm will stay longer in the race, while the small firm will quit earlier. The large firm's optimal stopping time is not affected by the competition, while the small firm's stopping time is reduced. Additionally, I find that companies will remain longer in the race if the investigation cost is lower, the winning premium is higher, the deadline is extended further, and the hazard rate is more prominent. Moreover, the market becomes more efficient with the competition since the patent is easier to realize. / Doctor of Philosophy / In this research, I study the consumer's behavior when individuals have limited cannot or do not give the same attention to each alternative available to them. In my study, I characterize the alternative-dependent focal Luce model (ADFLM), a consumer behavior model. Moreover, I solve the seller's profit maximization problem when the consumer's behavior follows the ADFLM. Meanwhile, I also study a dynamic patent race problem that occurs when firms compete for a patent with a deadline. If no firms achieve the patent, the stopping time (when the firm quits the patent race) of the large firm's (with a higher success rate every period) is not affected by the introduction of the small firm. However, the small firm quits earlier when the large firm is introduced. The competition between the two companies increases the overall probability of receiving a patent.

Algorithmically designed reward functions can influence groups of learning agents toward measurable desired sequential joint behaviours. Influencing learning agents toward desirable behaviours is non-trivial due to the difficulties of assigning credit for global success to the deserving agents and of inducing coordination. Quantifying joint behaviours lets us identify global success by ranking some behaviours as more desirable than others. We propose a real-valued metric for turn-taking, demonstrating how to measure one sequential joint behaviour. We describe how to identify the presence of turn-taking in simulation results and we calculate the quantity of turn-taking that could be observed between independent random agents. We demonstrate our turn-taking metric by reinterpreting previous work on turn-taking in emergent communication and by analysing a recorded human conversation. Given a metric, we can explore the space of reward functions and identify those reward functions that result in global success in groups of learning agents. We describe 'medium access games' as a model for human and machine communication and we present simulation results for an extensive range of reward functions for pairs of Q-learning agents. We use the Nash equilibria of medium access games to develop predictors for determining which reward functions result in turn-taking. Having demonstrated the predictive power of Nash equilibria for turn-taking in medium access games, we focus on synthesis of reward functions for stochastic games that result in arbitrary desirable Nash equilibria. Our method constructs a reward function such that a particular joint behaviour is the unique Nash equilibrium of a stochastic game, provided that such a reward function exists. This method builds on techniques for designing rewards for Markov decision processes and for normal form games. We explain our reward design methods in detail and formally prove that they are correct.